Drug resistant epilepsy (DRE) is defined as the persistence of seizures despite at least two syndrome-adapted antiseizure drugs (ASD) used at efficacious daily dose. Despite the increasing number of available ASD, about a third of patients with epilepsy still suffer from drug resistance. Several factors are associated with the risk of evolution to DRE in patients with newly diagnosed epilepsy, including epilepsy onset in the infancy, intellectual disability, symptomatic epilepsy and abnormal neurological exam. Pharmacological management often consists in ASD polytherapy. However, because quality of life is driven by several factors in patients with DRE, including the tolerability of the treatment, ASD management should try to optimize efficacy while anticipating the risks of drug-related adverse events. All patients with DRE should be evaluated at least once in a tertiary epilepsy center, especially to discuss eligibility for non-pharmacological therapies. This is of paramount importance in patients with drug resistant focal epilepsy in whom epilepsy surgery can result in long-term seizure freedom. Vagus nerve stimulation, deep brain stimulation or cortical stimulation can also improve seizure control. Lastly, considering the effect of DRE on psychologic status and social integration, comprehensive care adaptations are always needed in order to improve patients' quality of life.

About 25 antiseizure drugs are available for the treatment of patients with epilepsy. The choice of the most suited drug for a specific patient is primarily based on the results of the pivotal randomized clinical trials and on the patient’s characteristics and comorbidities. Whether or not the mechanism of action of the antiseizure drugs should be also taken into account to better predict the patient’s response to the treatment remains a matter of debate. Despite the apparent complexity and diversity of antiseizure drug mechanisms of action, the reality unfortunately remains that they are very close, in particular with regard to their relationship with the pathophysiology of epilepsy. With the only exception of the association between lamotrigine and sodium valproate, there are no clinical data that formally support a synergistic association between certain antiseizure drugs in terms of efficacy. However, anticipating risk of adverse events by limiting as far as possible the combination of drugs, which share the same mechanisms of action, is undoubtedly an important driver of daily therapeutic decisions.

Background and ObjectivesPrevious studies suggested that autoimmune limbic encephalitis with antibodies against contactin-associated protein-like 2 (CASPR2-encephalitis) is clinically heterogeneous and progresses slowly, preventing its early recognition. We aimed to describe the onset and progression of CASPR2-encephalitis and to assess long-term outcomes.MethodsWe retrospectively analyzed the medical records of all patients whose CSF tested positive for anti-CASPR2 antibodies in our center between 2006 and 2020. Standardized telephone interviews of all available patients and relatives were conducted, assessing long-term functional independence using the Functional Activity Questionnaire (FAQ) and quality of life using the 36-Item Short-Form Survey (SF36).ResultsForty-eight patients were included (98% males; median age 64 years), and 35 participated in telephone interviews (73%). At onset, 81% had at least 1 neurologic symptom among the following: limbic (54%), peripheral nerve hyperexcitability (PNH; 21%), and/or cerebellar symptoms (17%). Most of the patients (75%) had initially symptoms of only one of these categories. Limbic symptoms at onset included mostly seizures (33%), while memory disturbances were less frequent (10%). PNH signs were mostly neuropathic pain (9/10 patients). Other symptoms seen at onset included asthenia (33%), mood disorders (25%), and insomnia (21%); 19% of patients did not show any limbic, peripheral, or cerebellar symptom at onset but only asthenia (15%), mood disorders (6%), weight loss (8%), dysautonomia (4%), and/or insomnia (2%). The peak of the disease was attained in median 16.7 months after onset. Over the study period (median follow-up, 58.8 months, range 10.6–189.1), 77% of patients developed ≥3 core CASPR2 symptoms and 42% fulfilled the diagnostic criteria for autoimmune limbic encephalitis, although all patients ultimately developed limbic symptoms. At the last visit, most interviewed patients (28/35 patients, 80%; median, 5 years after onset) had recovered functional independence (FAQ <9) while only the vitality subscore of the SF36 was lower than normative data (mean 49.9 vs 58.0,p= 0.0369).DiscussionCASPR2-encephalitis has a progressive course and is highly heterogeneous at the early stage. In men older than 50 years, otherwise unexplained seizures, cerebellar ataxia, and/or neuropathic pain are suggestive of early-stage CASPR2-encephalitis, especially if they coincide with recent asthenia, mood disorders, or insomnia.